This is a basic scientific investigation of the patho-mechanistic etiology of post-traumatic osteoarthritis (PTOA) with particular emphasis on the role of acute mechanical damage. The long-term objectives of the study are to: 1)determine how acute mechanical damage is linked to PTOA;2) determine how acute mechanical damage affects the tolerance of articular cartilage to injury-associated changes in the long-term loading environment within a joint;and 3) investigate novel therapeutic options specifically designed to treat tissue-level and cellular-level damage associated with acutely impacted cartilage. A series of in vitro investigations will study the relative contribution of both acute damage and chronic loading abnormalities to cartilage degeneration. Potential adverse synergisitic interaction between these injury-associated residuals will also be investigated. Another in vitro study will investigate the role of matrix damage in the the cascade of injury propagation into surrounding uninjured cartilage. Finally, an established in vivo model will be used to investigate the patho-mechanistic link between acute mechanical damage, chronic abnormal loading, and the progression of PTOA, accounting for whole-joint effects that cannot be tested in parametric in vitro studies. The second part of the study will investigate therapeutic options that mechanically stabilize matrix damage and deliver targeted Pharmaceuticals into acutely damaged areas that foster chondrocytic anabolic metabolism and prevent chondrocyte apoptosis. These therapies will be studied in vitro, in a parametric study design that investigates treatment effectiveness with respect to impact energy and timing of treatment. To determine whole-joint effects, an in vivo porcine model of impact injury will be employed to study the same treatments. Post-traumatic osteoarthritis is a major cause of pain and dysfunction in a relatively young patient population. Therefore, it is also a major source of medical expenditure. Understanding the basic mechanisms that cause PTOA will facilitate development of more effective treatments. This study not only will further understanding the etiology of this devastating disease, it will provide new knowledge in a different treatment approach, focused on treating the acute mechanical damage. This study will investigate why injured joints develop arthritis. Furthermore, this study will investigate new treatment options that could potentially reduce or prevent arthritis in an injured joint.